tbuckley/cabot-search huggingface dataset:
Abstract 5977: Evaluation of the potential combination regimens for q901, a clinical stage selective cdk7 inhibitor, as a DNA damage repair inhibitor
Authors: Donghoon Yu, Yeejin Jeon, YoonJi Lee, Seung-Joo Lee, Jaeseung Kim, Hyerim Jung, Tae-Kyung Kim, Kiyean Nam
Journal: Cancer Research (2023)

Abstract Background; Q901 is an extremely selective CDK7 inhibitor with potent single agent activity in the multiple in vivo tumor models including small cell lung cancer, cholangiocarcinoma, colon cancer, pancreatic cancer, hormone receptor positive breast cancer, castrate-resistant prostate cancer, and ovarian cancer. Q901 is currently in Phase 1/2 clinical trial for patients with selected advanced solid tumors (ClinicalTrials.gov: NCT05394103). In the preclinical models, Q901 treatment induces DNA damage response (DDR) impairment markers, particularly ones involved in the double-strand break repair mechanisms. This opens up broad range of possibilities for new combination regimen that could benefit from the accumulated DNA damages caused by Q901 treatment. Methods: Various combinations have been tested to evaluate potential clinical regimens in multiple solid tumor models. Two different BRCA wild-type ovarian cancer A2780 and OVCAR3 models, an estrogen receptor positive MCF7 breast cancer model, or a syngeneic RENCA mouse renal cancer model was tested with Q901 in combination with poly ADP-ribose polymerase (PARP) inhibitor, selective estrogen receptor degrader (SERD), an estrogen receptor (ER) PROTAC degrader, or an anti-PD-1 antibody, respectively. Results: In the A2780 model, the PARPi alone group showed 15% TGI (tumor growth inhibition), but significant tumor regression (104% TGI) was observed in the Q901 and PARPi combination. In the OVCAR3 model, the Q901 and PARPi combination group showed 105% TGI, whereas the PARPi alone group showed 38% TGI. In the MCF7 model, SERD alone showed 64% TGI and Q901 combination with SERD showed 94% TGI. Remarkable tumor regression (111% TGI) was observed in the MCF7 model combining ER PROTAC and Q901, whereas ER PROTAC alone group showed 55% TGI. In the RENCA model, the anti-PD-1 antibody alone group showed 13.2% TGI and the combination of Q901 and anti-PD-1 antibody showed 66% TGI. In summary, these preclinical model studies demonstrated significant additive/synergistic effects of the Q901 combination on tumor growth inhibition. Conclusion: The non-clinical data demonstrate that Q901 not only has a potential as a single agent,but can also be used in combination with other therapeutic strategies to develop next-generation cancer therapeutics to potentially address unmet medical needs. Citation Format: Donghoon Yu, Yeejin Jeon, YoonJi Lee, Seung-Joo Lee, Jaeseung Kim, Hyerim Jung, Tae-Kyung Kim, Kiyean Nam. Evaluation of the potential combination regimens for q901, a clinical stage selective cdk7 inhibitor, as a DNA damage repair inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5977.
Abstract 19: Braf(v600e) mutation together with loss of trp53 or pten drives the origination of hairy cell leukemia from b-lymphocyte
Authors: Jiajun Yap, Jimin Yuan, Bin Gao Chen, Wan Hwa Ng, Yuen Rong M. Sim, Kah Chun Goh, Jiancheng Hu
Journal: Cancer Research (2023)

Abstract Hairy cell leukemia (HCL) is a B-lymphoma induced by BRAF(V600E) mutation. However, introducing BRAF(V600E) in B-lymphocytes fails to induce hematological malignancy, suggesting that BRAF(V600E) needs concurrent mutations for driving HCL ontogeny. To resolve this issue, here we surveyed the human HCL genomic sequence data. Together with previous reports, we speculated that tumor suppressor, Trp53, P27, or pTEN restricted the oncogenicity of BRAF(V600E) in B-lymphocytes, whose loss-of-function facilitates the BRAF(V600E)-driven HCL ontogeny. Using genetic mice models, we demonstrated that indeed BRAF(V600E)KI together with Trp53KO or pTENKO in B-lymphocytes induced chronic lymphoma with pathological features of human HCL. To further understand cellular programs essential for HCL ontogeny, we next profiled the gene expression of leukemic cells isolated from BRAF(V600E)KI and Trp53KO or pTENKO mice, and found that these leukemic cells had similar but different gene expression signatures that resemble that of M2 or M1 macrophages. In addition, we examined the expression signature of transcription factors/regulators required for germinal center reaction and memory B cell versus plasma cell differentiation in these leukemic cells and found that most transcription factors/regulators essential for these programs were severely inhibited, which illustrates why hairy cells are arrested at a transitional stage between activated B cells and memory B cells. Together, our study has uncovered concurrent mutations for HCL ontogeny, revealed the B cell origination of hairy cells as well as molecular basis that underlies unique pathological features of this disease, and hence has important implications in both HCL research and clinic treatment. Citation Format: Jiajun Yap, Jimin Yuan, Bin Gao Chen, Wan Hwa Ng, Yuen Rong M. Sim, Kah Chun Goh, Jiancheng Hu. Braf(v600e) mutation together with loss of trp53 or pten drives the origination of hairy cell leukemia from b-lymphocyte [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 19.
Abstract 1941: Barriers and effective interventions to engage Latinas' participation in breast cancer clinical trials
Authors: Monica J. Padilla, Gregory Karczmar
Journal: Cancer Research (2023)

Abstract Breast cancer is the most diagnosed cancer among Latina women and is the leading cause of cancer-related death among Latinas (16.6%). While The Latino population is one of the fastest-growing populations in the US, they are severely underrepresented in clinical trials. Latinos make up 17% of the population but only 1% of clinical trial participants. Of clinical trials published covering 2001-2010, Latinos’ enrollment constituted only 2.2% of accrued participants. The percentage of Latino participants narrows down when we separate by gender. The goal of this study is to examine the prevalence of breast cancer-related barriers among Latinas and to determine the extent to which these barriers might influence Latinas enrolling in breast cancer clinical trials. If language and religion are the reason Latinas enroll less in breast cancer clinical trials, then increasing the availability of translated materials and a priest of a Catholic Church advertising the breast cancer studies will increase the enrollment rate of Latinas. Semi-constructed interviews were conducted with two Latino organizations to understand current barriers Latina’s face within the medical field. Based on these findings, I conducted an intervention at Our Lady of Tepeyac Church consisting of an information booth, making an announcement regarding Research Study 9127, and having bilingual Latinas available to give out more information while helping them enroll in Research Study 9127. At the end of the church intervention, 33 Latinas were enrolled in Research Study 9127, seeing a 550% increase in Latinas participating in Research Study 9127. Latinx women remain severely underrepresented in breast cancer clinical trials, thus limiting the generalizability of cancer clinical research, but interventions across churches would lead to improvements in general cancer knowledge, breast cancer screening practices, and intentions to enroll in clinical trials. This study can inform efforts to increase clinical trial participation in Latinas by highlighting important motivators to participation specific to Latinas and informing future interventions aimed at encouraging participation in clinical trials in a culturally sensitive and effective way. Citation Format: Monica J. Padilla, Gregory Karczmar. Barriers and effective interventions to engage Latinas' participation in breast cancer clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1941.
Abstract 6424: Immune characteristics and anti-PD-1-induced reinvigoration capacity of tumor-infiltrating lymphocytes in ovarian clear cell carcinoma relative to high-grade serous ovarian carcinoma
Authors: Junsik Park, Yong Jae Lee, Jung Chul Kim, Jung-Yun Lee
Journal: Cancer Research (2023)

Abstract Recent clinical trials have demonstrated the potential efficacy of immune checkpoint inhibitors (ICIs) for ovarian clear cell carcinoma (OCCC). However, little is known about the immune characteristics of OCCC. In this study, we aimed to investigate the distinct immune characteristics of tumor-infiltrating lymphocytes (TILs) in OCCC to high-grade serous ovarian carcinoma (HGSOC). We isolated peripheral blood mononuclear cells (PBMCs) and TILs from patients with epithelial ovarian cancer. The expression of immune checkpoint receptors and T-cell transcription factors of TILs in OCCC (n=26) and HGSOC patients (n=44) were accessed using flow cytometry. TILs were ex vivo stimulated with anti-CD3 in the presence of anti-PD-1 and/or anti-CTLA-4, and their proliferation was assessed to predict response to ICIs. CD8 TILs and tumor-infiltrating regulatory T cells (Tregs) exhibited higher expression of immune checkpoint receptors, including PD-1, CTLA-4, and 4-1BB, compared to PBMCs. Tregs were more infiltrated in advanced/recurrent stage than early stage OCCC. However, immune characteristics of CD8 TILs and Tregs were not significantly different regardless of stage. When we compared the characteristics of TILs in OCCC (n=26) with those in HGSOC (n=44), the expression of PD-1 on CD8 TILs was significantly lower in OCCC than in HGSOC. The frequencies of PD-1highCD8 TILs and PD-1+TOX+CD8 TILs were also lower in OCCC than HGSOC. In ex vivo assay (n=19), 9 cases responded to anti-PD-1 in terms of enhanced proliferation capacity of CD8 TILs. In addition, when anti-CTLA-4 was added to anti-PD-1, an additional increase in proliferation of CD8 TILs was observed in patients who responded to anti-PD-1. Responders to anti-PD-1 had significantly lower frequencies of effector Tregs in the TILs than non-responders. Overall, CD8 TIL in OCCC was found to be less exhausted than HGSOC in terms of PD-1 and TOX expressions. Tumor-infiltrating Tregs affected on reinvigoration ability of CD8 TILs upon ICIs treatment in OCCC. This study provides the rationale and evidence for establishing the optimal strategies for ICIs treatment in patients with OCCC. Citation Format: Junsik Park, Yong Jae Lee, Jung Chul Kim, Jung-Yun Lee. Immune characteristics and anti-PD-1-induced reinvigoration capacity of tumor-infiltrating lymphocytes in ovarian clear cell carcinoma relative to high-grade serous ovarian carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6424.
Abstract 5879: Defining the cancer Immunogram using multimodal analysis to guide immunotherapy in diffuse large B cell lymphoma
Authors: Michael D. Mattie, Regis Perbost, Sarah Turcan, Corinne Danan, Frederick L. Locke, Sattva S. Neelapu, David B. Miklos, Caron A. Jacobson, Lazaros J. Lekakis, Yi Lin, Armin Ghobadi, Jenny J. Kim, Zixing Wang, Allen Xue, Simone Filosto, Nathalie Scholler, Jerome Galon
Journal: Cancer Research (2023)

Abstract (a) Expansion of therapeutic strategies against diffuse large B-cell lymphoma (DLBCL) offers new opportunities to fight aggressive non-Hodgkin's lymphoma. Therapy approaches, such as R-CHOP and stem cell transplant, and CAR-T cell therapies are now available for the treatment of DLBCL. While the role of the tumor microenvironment (TME) during the therapeutic response is now recognized, the spatial organization and the communication between the diverse factors that compose the TME remains to be fully understood. In this study, we describe a new immunogram tool to help clinical researchers measure the tumor microenvironment contribution to drug efficacy or toxicity in DLBCL context. (b) In a previous work, using a high-quality testing and innovative multimodal and integrative approach, we constructed the first Veracyte Biopharma Atlas for DLBCL lesions. Based on this knowledge and the understanding of the immune contexture of tumors, we constructed an immunogram using the scoring of clinically relevant biomarkers. Our immunogram scoring approach is composed of key features driving computational derivation of DLBCL Atlas clusters, which include immune gene signatures, immune cell phenotyping combined with spatial information, and genomic and clinical parameters. (c) Patterns that strongly associated with CAR-T treatment response were determined. In addition, promising results have been obtained in the prediction to CAR-T toxicity related to T-regulatory cells or R-CHOP response with transcriptomic signature. (d) Retrospective analysis of CAR-T clinical trial data and tumor biopsies highlighted the Veracyte Immunogram as a powerful tool to score the patient probability of response to CAR-T. This work provides the framework for identification of predictors of response to therapy, potential targets of interest or biomarkers that could be applied in future clinical trials. Citation Format: Michael D. Mattie, Regis Perbost, Sarah Turcan, Corinne Danan, Frederick L. Locke, Sattva S. Neelapu, David B. Miklos, Caron A. Jacobson, Lazaros J. Lekakis, Yi Lin, Armin Ghobadi, Jenny J. Kim, Zixing Wang, Allen Xue, Simone Filosto, Nathalie Scholler, Jerome Galon. Defining the cancer Immunogram using multimodal analysis to guide immunotherapy in diffuse large B cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5879.
Abstract 6557: A 6-microbial signature risk score for overall survival prediction in hepatocellular carcinoma: a machine learning approach
Authors: Nour N. Al-Bzour, Ayah N. Al-Bzour
Journal: Cancer Research (2023)

Abstract Introduction: Hepatocellular carcinoma (HCC) is a severe type of cancer associated with high malignancy and poor prognosis. To reach a better prognosis, several factors affecting HCC patients must be considered. In this study, we aim to investigate the relationship between gut microbiota with the survival of HCC patients, and to build a machine learning (ML) prognostic model based on microbiome signatures. Methods: Microbial and survival data for HCC patients from The Cancer Genome Atlas Program (TCGA) were obtained using the cBioportal database. The microbiome signatures were screened for prognostic effect using the univariate cox regression. The significant microbial signatures were fitted into the Least Absolute Selection and Shrinkage Operator - Cox (LASSO-Cox) model to reduce multicollinearity. Signatures with non-zero LASSO coefficients were screened for independent effect in the multivariate cox regression analysis. Results: A total of 1407 microbial signatures were downloaded from TCGA dataset. 63 prognostic microbial signatures were identified using the univariate cox. A total of 30 prognostic microbial signatures were screened out using LASSO and further evaluated using independent effect to obtain microbiome risk score. Six microbial signatures were identified as independent prognostic markers including: Marichromatium (HR: 1.26; 95%CI: [0.01-1.56]), p=0.038), Paraclostridium (HR: 1.45; 95%CI:[1.15-1.82], p=0.002), Pseudorhodoferax (HR: 1.20; 95%CI:[1.01-1.43], p=0.037), Chitinimonas (HR: 1.47 95%CI: [1.10-1.97], p=0.009), Marinobacter (HR: 0.79; 95%CI: [0.65-0.97], p=0.022), Desulfovermiculus (HR: 1.44; 95%CI: [1.16-1.78, p=0.001]). Kaplan-Meier survival plot showed better overall survival (OS) in the low-risk group compared to the high-risk group (median OS: 83.6 vs. 41.8; log-rank p-value &amp;lt;0.0001). Conclusion: Our results show that the gut microbiota is significantly associated with HCC prognosis, in which 5 of them were associated with poorer prognosis and one was associated with better survival. These microbial signatures provide a potential prognostic marker for HCC survival. Citation Format: Nour N. Al-Bzour, Ayah N. Al-Bzour. A 6-microbial signature risk score for overall survival prediction in hepatocellular carcinoma: a machine learning approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6557.
Abstract 4667: Establishment of patient-derived human cell lines using PDX mouse model for intrahepatic cholangiocarcinoma
Authors: Takashi Matsumoto
Journal: Cancer Research (2023)

Abstract Background: In recent years, patient tumor transplant models (PDX models) have attracted method that can predict the effects of anticancer drugs on patients. The PDX model is a technique in which the patient's tumor tissue is directly transplanted into immunodeficient mice. Tumors can grow three-dimensionally in a living mouse, so compared to culturing in petri dishes, the situation is like the growth of tumors in the patient's body. In addition, there are reports that the efficacy of anticancer drugs in patients and the results of administration of anticancer drugs in PDX show a high concordance rate, and it is attracting attention as a model that can predict efficacy in patients. In this time, we report on the establishment of cell lines using PDX mice for resected cases of intrahepatic cholangiocarcinoma in our hospital. Methods: Twelve patients who underwent surgical resection between September 2019 and December 2021 were included. After resected the tumor, the tumor was transplanted into up to 10 PDX mice, and cell lines were established from the formed tumor tissue. Results: Of the 12 cases, tumors formed in PDX mice after transplantation in 6 cases, and the median time to engraftment after the first transplantation was 133 days (75-188). Furthermore, among the 6 cases, 3 cases achieved the establishment of cell lines.Case1:moderately differentiated adenocarcinoma, tumor diameter 50mm, single, vascular invasion positive, no lymph node metastasis, Stage IIIA (UICC 8th)Case2:well differentiated adenocarcinoma, tumor diameter 60mm, single, vascular invasion negative, no lymph node metastasis, Stage II (UICC 8th)Case 3:moderately differentiated adenocarcinoma, tumor diameter 55mm, single, vascular invasion positive, no lymph node metastasis, Stage IIIA (UICC 8th) Conclusion: The cell line we established this time is a case of advanced cancer, and we would like to continue to increase the number of cases and continue to establish cell lines, which will lead to future research. Citation Format: Takashi Matsumoto. Establishment of patient-derived human cell lines using PDX mouse model for intrahepatic cholangiocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4667.
Abstract 1373: Cell-in-cell mediated entosis reveals a progression mechanism in pancreatic cancer
Authors: Jianlu Song, Rexiati Ruze, Yuan Chen, Ruiyuan Xu, Xinpeng Yin, Chengcheng Wang, Yupei Zhao
Journal: Cancer Research (2023)

Abstract Pancreatic cancer (PC) is a deadly malignancy with high intra-tumoral heterogeneity and lacks effective therapeutics. Entosis is a non-apoptotic regulated cell death mediated by cell-in-cell (CIC) structures. However, the impact of entosis on PC progression needs to be determined. This study analyzes the expression levels and prognostic values of entosis-related regulators in public datasets. It identifies that these regulators are commonly upregulated in PC and associated with worse prognosis. We further find that the entotic CIC structures detected in PC specimens have a possible correlation with PC metastases. We enrich a cell population of PC cells undergoing entotic CIC using fluorescence-activated cell sorting (FACS), and several oncogenes, such as NET1, ALDH3A1, PLAT, GALNT5, and FAM3C, were defined as the marker genes of this population using single-cell RNA sequencing (scRNA-seq) analysis. Functionally, this population demonstrates enhanced cell proliferation, migration, invasion, anoikis resistance, sphere formation in vitro, and tumorigenicity in vivo. Moreover, NET1 (neuroepithelial cell transforming gene 1) overexpression promotes cell proliferation, migration, invasion, anoikis resistance, CIC formation, cell competition in vitro, and tumorigenicity in vivo of PC cells. NTE1 is also associated with unfavorable prognosis for PC patients. These results indicate that entosis may play a vital oncogenic role in PC progression. PC cells generate a highly “progressive” subpopulation marked by NET1 via entotic CIC. NET1 is a newly validated gene related to entosis. Targeting entotic processes may be a potential therapeutic option for PC. Citation Format: Jianlu Song, Rexiati Ruze, Yuan Chen, Ruiyuan Xu, Xinpeng Yin, Chengcheng Wang, Yupei Zhao. Cell-in-cell mediated entosis reveals a progression mechanism in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1373.